STRESS, EXERCISE, AND EPIGENETICS: SEEING PAST ADVERSITY

Abstract

Experiences during critical and sensitive periods of development can have lasting effects on brain health and function. Stressful experiences during this time can disrupt early neural processes, such as synaptogenesis and synaptic pruning, which can make individuals more susceptible to psychiatric disorders, such as depression, anxiety, schizophrenia, and bipolar disorder late in life. Today we understand these experiences impact the brain in part through epigenetic mechanisms. Epigenetics refers to changes in gene expression without altering the underlying DNA sequence, with DNA methylation being a key mechanism. During DNA methylation, methyl groups are attached to cytosine-guanine dinucleotides, typically leading to gene silencing, especially when methylation surrounds the promoter region of the gene. Stress during early life has been noted to increase DNA methylation of the brain-derived neurotrophic factor (Bdnf) gene, ultimately reducing BDNF protein levels. Down regulation of BDNF production can have a profound effect on brain development and behavioral regulation. Dysregulation of the Bdnf gene is linked to the etiology of many psychiatric disorders, including depression and bipolar disorder. Conversely, adaptive experiences, such as exercise, are associated with increased Bdnf expression and reduced symptoms of anxiety and depression. Exercise may be further neuroprotective by enhancing synaptogenesis and other processes that improve the brain’s resilience against neurodegeneration. Recent studies have begun investigating the potential of exercise to counteract the maladaptive effects of early life stress via changes in Bdnf expression. In the Roth Lab, we utilize a preclinical rodent model to elucidate how early adverse experiences affect brain development through epigenetic changes, focusing on better understanding treatments that may mitigate these effects. Importantly, stress during infancy in rodents often leads to decreased Bdnf activity, which is associated with behavioral abnormalities and increased Bdnf methylation in these models. Ultimately, Bdnf has become an important target when understanding the relationship between stress, therapeutic interventions, and behavior. Preclinical work in this arena may eventually help develop interventions for mitigating the impacts of early insults on human brain development. In our experiments here, we utilized a resource-scarce environment to induce fragmented maternal care and aversive behaviors from the rodent dam towards the pups. We then sought to determine if voluntary exercise was an efficacious intervention to bolster neural resilience. We also explored a mechanism proposed to underlie exercise-induced changes in Bdnf expression. Chapter 1 of this dissertation provides a comprehensive introduction to the impacts of early life stress on brain and behavior development, the rationale behind exercise therapy, and the implications of epigenetic mechanisms, with a focus on Bdnf. Chapter 2 sought to elucidate changes in Bdnf gene methylation and expression in the adult prefrontal cortex as a function of early life stress (ELS), young adult exercise, and sex. On postnatal day (PN) 1, rat pups were randomly assigned to one of three infant care groups— normal maternal care (NMC), cross-foster care (CFC), and maltreatment (MAL). Pups in the NMC condition remained in the homecage with their biological mother, or dam. In contrast, pups in the CFC and MAL groups were placed with non-biological dams and moved to different chambers for 30-minutes per day for the first 7 days of life. However, the CFC dam was given ample time to habituate to the novel environment and was provided with copious bedding and nesting materials to care for pups. The MAL dam, on the other hand, was not given time to habituate, nor was she given bedding and nesting materials. This model, termed the scarcity- adversity model, elicits adverse behaviors from the MAL dam towards the pups and decreases her nurturing care behaviors. In young adulthood, some of these pups were given access to voluntary running wheels for 20 days, until brain extractions on PN90. Our results showed that exercise alters the epigenetic landscape of the Bdnf gene in an exon- and sex-specific manner, and is influenced by early life experiences, within the adult prefrontal cortex (PFC). Briefly, we noted exercise in adulthood largely has no immediate effect on Bdnf exon I methylation, suggesting this locus may not be involved in exercise-induced Bdnf gene regulation, but that exercise does decrease methylation at Bdnf exons IV and IX. Changes at exon IV and IX were influenced by sex and the early life environment, respectively. Chapter 3 followed nearly the exact same experimental design as Chapter 2, the only exception being that the exercise exposure occurred for 20 days during adolescence. Brains were still extracted at PN 90 to determine if an exercise intervention during a time of high neural plasticity would alter the Bdnf epigenetic landscape in the PFC long after the intervention ended. Our results showed that exercise lowered Bdnf exon I and IX methylation, and that ELS increased methylation of exon IV in female but not male rats. We further observed changes in some social behaviors as a function of exercise exposure and sex. Finally, Chapter 4 sought to determine if our model of ELS and adolescent exercise affected magnetic resonance imaging (MRI) metrics using diffusion MRI (dMRI). Similar to Chapters 2 and 3, rat pups were assigned to the CFC or MAL conditions. For these experiments, we omitted the NMC group and male rats due to budget and time constraints. We chose to use the CFC as our control group (rather than NMC), as this condition is most comparable to the MAL group. Pups in the CFC and MAL conditions are handled similarly by the experimenter and both are placed with non-biological dams. Maternal behavior was recorded with pups in the Chapter 2 experiment, as some female subjects from those litters were assigned to this MRI experiment rather than the epigenetics experiment. In Chapter 4, we utilized two pilot studies with longitudinal study designs. In experiment 1, after weaning on PNs 21-23, pups were pairhoused with a non-littermate of the same infant condition. dMRI scans were acquired on PNs 25 and 65 in Experiment 1 and PNs 27 and 55 in Experiment 2 to measure potential effects of stress at early and late/end of adolescence. Our overall results revealed that regional volume and structural integrity change with age, with some minimal effects of stress and exercise.